Diuretics Flashcards
How do sodium and water move across the proximal tubule epithelium?
- Na channels on apical membrane allow Na to diffuse into epithelial cell
- Water follows by osmosis
- Na/K ATPase pumps Na out of cell into blood
- Oncotic pressure exerted by proteins in blood draws water into capillaries
- Na and water move via paracellular pathway
- Bicarbonate ions reabsorbed into capillaries along w/Na (Na/HCO3 cotransport)
- Na/H+ exchanger on apical membrane (H+ from CA activity inside cell)
What happens in the descending limb of LOH?
Water moves from isotonic tubular fluid across epithelial cell to hypertonic interstitium
Freely permeable to water
What happens in the ascending limb of LOH?
- Impermeable to water
- Na/K/Cl transporter moves these ions into epithelial cell from tubular fluid
- Na/K ATPase and K/Cl cotransporter moves these ions into interstitium
- Some paracellular Na diffusion into interstitium
What happens in the distal tubule?
Early distal tubule - any Na left in filtrate is transported by Na/Cl transporter in apical membrane, and eventually enters capillaries
Late - aldosterone and aquaporins become more important
What happens in the collecting duct?
Aldosterone binds to mineralocorticoid receptors in cell and acts via nucleus to increase production of Na channels and Na/K ATPase –> increased Na reabsorption
Vasopressin synthesises and assembles AQP2 molecules that allow water to cross apical membrane and follow Na
How do diuretics work?
- Most inhibit reabsorption of Na and Cl (increase excretion) - water follows
- Increase osmolarity of tubular fluid - decrease osmotic gradient across epithelia
What are the 5 main classes of diuretic drugs?
- Osmotic diuretics
- Carbonic anhydrase inhibitors
- Loop diuretics
- Thiazide diuretics
- Potassium-sparing diuretics
How do osmotic diuretics work?
E.g. mannitol
- Have the same effect thr/o nephron
- Pharmacologically inert
- Filtered by glomerulus but not reabsorbed
- No action on Na reabsoprtion
- Increase osmolarity of tubular fluid
- Tf decreased H20 reabsorption where nephron is permeable to water (PCT, descending LOH, CD)
- Less water leaves lumen and is reabsorbed
How do carbonic anhydrase inhibitors work?
E.g. acetazolamide
- Block CA
- Prevents H+ and HCO3- entering epithelial cells from lumen
- Tf less Na/H+ exchange on apical membrane
- Bicarbonate remains in lumen –> less Na reabsorbed
- Water remains in lumen
- Increases urine volume
How do loop diuretics work?
E.g. frusemide
- Inhibit Na, HCO3- reabsorption in PCT
- Increase tubular fluid osmolarity
- Decrease osmolarity of medullary interstitium –> decrease H20 reabsorption in CD
- Increase delivery of HCO3- in to distal tubule –> increases K loss
- Ca and Mg - loss of K recylcing
- Act on ASCENDING LOH
- Target Na/K/Cl triple transporter
What is potassium recycling?
- Proximal tubule and LOH
- K is constantly reabsorbed and lost across membrane btwn tubule lumen and cell
- Constantly replenishing certain amount of positive charge to lumen
- Constantly adding K as well as Na, Ca, Mg means there’s a large net positive charge in lumen
- Paracellular route btwn ascending limb cells –> some K, Mg, Na moves thr to interstitium bc positive charge pushes +ve ions away (thr paracellular route)
- If you interfere with K recycling (CA inhibitors, loop diuretics) –> reduce some K movement, reduce some excess positive lumen charge –> less K, Na, Mg moves thr paracellular route –> lose more Na (expected), but also Ca, Mg
How do thiazide diuretics work?
E.g. bendroflumethiazide
- Bind to and block Na/Cl cotransporter
- Inhibit Na, Cl reabsorption in early distal tubule
- Increase Na delivery to later parts of distal tubule –> increased K loss (Na/K exchanger)
- Increase Mg excretion, Ca reabsorption (cause unknown)
- Increase tubular fluid osmolarity –> decrease water reabsorption in CD
What is the problem with thiazide and loop diuretics?
- Over time, they cause hyponatraemia (expected)
- One stimulus for renin secretion = low Na in tubule
- Lower Na load passing thr lumen –> diuretics promote renin secretion
- If you want diuretic effect, increasing renin secretion isn’t helpful
- Renin increases aldosterone –> aldosterone promotes Na, Cl reabsorption
- Macula densa has same target as target loop diuretics act on (Na/Cl/K transporter)
- Loop diuretics indirectly influence renin (above) AND directly affect renin by stopping Na entering macula densa cells
How do potassium sparing diuretics work?
- Inhibit Na reabsorption (and concomitant K secretion) in late distal tubule
- Increase tubular fluid osmolarity
- Leads to decrease in water reabsorption in CD
- Increase H+ retention (due to reduced Na/H exchange)
- Increase loss of uric acid
How can diuretics be used to treat hypertension?
- Thiazides are 1st line treatment in most countries
- 1st line treatment in patients over 55 and Afro Caribbeans of any age in UK
- Initial BP drop in 4-6 weeks due to drop in plasma volume
- After 4-6 weeks, plasma volume is restored (renin problem)
- Chronic thiazides have vasodilatory effect –> decrease TPR –> activation of eNOS, Ca channel antagonism, opening Kca channel (smooth muscle) ALL –> BP drop
